PMID- 28604807 OWN - NLM STAT- MEDLINE DCOM- 20170926 LR - 20181113 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 12 IP - 6 DP - 2017 TI - Brain-derived neurotrophic factor (BDNF) -TrKB signaling modulates cancer-endothelial cells interaction and affects the outcomes of triple negative breast cancer. PG - e0178173 LID - 10.1371/journal.pone.0178173 [doi] LID - e0178173 AB - AIMS: There is good evidence that the tumor microenvironment plays an important role in cancer metastasis and progression. Our previous studies have shown that brain-derived neurotrophic factor (BDNF) participates in the process of metastasis and in the migration of cancer cells. The aim of this study was to investigate the role of BDNF on the tumor cell microenvironment, namely, the cancer cell-endothelial cell interaction of TNBC cells. METHODS: We conducted oligoneucleotide microarray analysis of potential biomarkers that are able to differentiate recurrent TNBC from non-recurrent TNBC. The MDA-MB-231 and human endothelial HUVEC lines were used for this study and our approaches included functional studies, such as migration assay, as well as Western blot and real-time PCR analysis of migration and angiogenic signaling. In addition, we analyzed the survival outcome of TNBC breast cancer patients according to their expression level of BDNF using clinical samples. RESULTS: The results demonstrated that BDNF was able to bring about autocrinal (MDA-MB-231) and paracrinal (HUVECs) regulation of BDNF-TrkB gene expression and this affected cell migratory activity. The BDNF-induced migratory activity was blocked by inhibitors of ERK, PI3K and TrkB when MDA-MB-231 cells were examined, but only an inhibitor of ERK blocked this activity when HUVEC cells were used. Furthermore, decreased migratory activity was found for big up tri, openBDNF and big up tri, openTrkB cell lines. Ingenuity pathway analysis (IPA) of MDA-MB-231 cells showed that BDNF is a key factor that is able to regulate a network made up of metalloproteases and calmodulin. Protein expression levels in a tissue array of tumor slices were found to be correlated with patient prognosis and the results showed that there was significant correlation of TrkB expression, but not of BDNF. expressionwith patient DFS and OS. CONCLUSION: Our study demonstrates that up-regulation of the BDNF signaling pathway seems tobe involved in the mechanism associated with early recurrence in triple negative breast cancer cell. In addition, BDNF can function in either an autocrine or a paracrine manner to increase the migration ability of both MDA-MB-231 cells and HUVEC cells. Finally, overexpression of TrkB, but not of BDNF, is significantly associated with a poor survival outcome for TNBC patients. FAU - Tsai, Yi-Fang AU - Tsai YF AD - Comprehensive Breast Health Center & Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China. AD - Institute of Clinical Medicine, Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China. FAU - Tseng, Ling-Ming AU - Tseng LM AD - Comprehensive Breast Health Center & Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China. AD - Department of Surgery, School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China. FAU - Hsu, Chih-Yi AU - Hsu CY AD - Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taiwan, Republic of China. AD - School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China. FAU - Yang, Muh-Hwa AU - Yang MH AD - Institute of Clinical Medicine, Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China. AD - Division of Medical Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China. AD - Genomic Medicine Research Center, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China. FAU - Chiu, Jen-Hwey AU - Chiu JH AUID- ORCID: 0000-0003-3046-6250 AD - Comprehensive Breast Health Center & Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China. AD - Division of General Surgery, Department of Surgery, Cheng-Hsin General Hospital, Taipei, Taiwan, Republic of China. AD - Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China. FAU - Shyr, Yi-Ming AU - Shyr YM AD - Comprehensive Breast Health Center & Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China. AD - Department of Surgery, School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China. LA - eng PT - Journal Article DEP - 20170612 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Membrane Glycoproteins) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 2.7.10.1 (tropomyosin-related kinase-B, human) SB - IM MH - Brain-Derived Neurotrophic Factor/*metabolism MH - *Cell Communication MH - Cell Line, Tumor MH - Cell Movement MH - Cell Proliferation MH - Databases, Nucleic Acid MH - Endothelial Cells/*metabolism MH - Female MH - Gene Expression Profiling MH - Gene Regulatory Networks MH - Humans MH - Membrane Glycoproteins/*metabolism MH - Neoplasm Staging MH - Prognosis MH - Receptor, trkB/*metabolism MH - *Signal Transduction MH - Survival Analysis MH - Triple Negative Breast Neoplasms/genetics/*metabolism/*mortality/pathology PMC - PMC5467823 COIS- Competing Interests: The authors have declared that no competing interest exist. EDAT- 2017/06/13 06:00 MHDA- 2017/09/28 06:00 PMCR- 2017/06/12 CRDT- 2017/06/13 06:00 PHST- 2017/01/12 00:00 [received] PHST- 2017/05/08 00:00 [accepted] PHST- 2017/06/13 06:00 [entrez] PHST- 2017/06/13 06:00 [pubmed] PHST- 2017/09/28 06:00 [medline] PHST- 2017/06/12 00:00 [pmc-release] AID - PONE-D-17-01456 [pii] AID - 10.1371/journal.pone.0178173 [doi] PST - epublish SO - PLoS One. 2017 Jun 12;12(6):e0178173. doi: 10.1371/journal.pone.0178173. eCollection 2017.